Chiral substituted tetrahydroquinoline derivatives possess variety of pharmacological activities and hence, the current trend of research is looking for efficient methods for the construction of these derivatives. There is ample literature available on the construction of chiral tetrahydroquinoline derivatives. The 1,2,3,4-tetrahydroquinoline (THQ) is a very common structural motiff found in numerous biologically active natural products and pharmacologically relevant therapeutic agents. For example, (−)-sumanirole [PNU-95666E, (1)] is a selective and high affinity agonist at the dopamine D2 receptor subtype and has proven as a potential agent for the treatment of Parkinson's disease and restless leg syndrome. Also, 1-[(S)-3-(dimethylamino)-3,4-dihydro-6,7-dimethoxy quinolin-1(2H)-yl]propanone [(S)-903 (2)] has recently been identified as a potentially interesting positive inotropic agent, while (+)-duocarmycin D1 (3) has exhibited potent antitumor activity, whereas Anachelin H chromophore (3′) has significant anti-bacterial activity (FIG. 1). Due to the significance of these scaffolds in drug discovery and medicinal chemistry, the development of new methodologies for the synthesis of 3-substituted THQs derivatives continue to be very active field of research in recent years.

A few methods thus are reported in the literature for their synthesis. Rh-catalyzed reduction of chiral amino cinnamates by Isabelle Gallou-Dagommer et al. is reported in Org. Lett., 2001, 3 (13), pp 2053, whereas CoCl2-catalyzed reductive cyclization of nitro cyclic sulfites is disclosed in Org. Lett., 2009, 11 (4), pp 803-806 by Arun R. Jagdale. Also Co-catalyzed concise enantioselective synthesis of 1-[(S)-3-(dimethylamino)-3,4-dihydro-6,7-dimethoxyquinolin-1(2H)yl]propan-1-one, (S)-903 is reported in Tetrahedron: Asymmetry 20, (3), 2009, PP 335-339.
Romano Di Fabio et al. in Bioorganic a Medicinal Chemistry Letters 17 (5), 2007, 1176-80 discloses the preparation of chiral tetrahydroquinoline derivatives by an asymmetric Mannich-type condensation reaction using commercially available vinyloxyethylsilane and a N-arylimino R-(+)-t-butyl lactate ester, in the presence of a catalytic amount of metal triflates as Lewis acids.
Highly enantioselective chiral bifunctional thiourea catalyzed asymmetric tandem reactions for synthesis of substituted tetrahydroquinolines in good yields and high enantioselectivities are demonstrated by Zhen-Xin Jia in Org. Lett., 2011, 13 (5), pp 832-835. Further Young Ku Kang et al in J. Am. Chem. Soc., 2010, 132 (34), pp 11847-11849 describes CSA (Camphorsulfonic acid) mediated efficient formation of ring-fused tetrahydroquinolines in high enantioselectivities.
However, the use of expensive chiral starting materials, multi-step reaction sequences, use of protection and deprotection of various functional groups and low overall yields are some of the limitations of the existing routes. In this regard, an organocatalytic protocol that provides for the efficient synthesis of chiral 3-substituted THQs is highly desirable.
In recent years, it has been proven that proline-catalyzed direct α-aminooxylation or -amination of aldehydes provides efficiently for the enantioselective synthesis of α-amino acid derivatives. The highly enantioselective method for the synthesis of γ-amino-α,β-unsaturated esters via tandem α-amination-Horner-Wadsworth-Emmons (HWE) olefination of aldehydes is described in Org. Lett., 2007, 9 (6), pp 1001-1004 by Shriram P. Kotkar et al. Further organocatalytic sequential α-aminoxylation followed by cis-Wittig olefination of aldehydes is reported by Dattatray A. Devalankar Tetrahedron: Asymmetry Volume 23 Issues 3-4, 29 Feb. 2012, Pages 240-244. The organocatalytic sequential α-aminationcorey-chaykovsky reaction of aldehydes is reported by B. Senthil kumar in Org. lett., 2012, 14 (10), pp 2468-2471.
Yet, full synthetic potential of the use of α-functionalized aldehydes that are readily available in situ by existing route in excellent enantioselectivity, remains to be further explored.
In continuation of present work on the utilization and application of these enantiomerically-enriched α-functionalized aldehydes, the present inventors have succeeded to develop sequential reaction of α-aminooxylation or -amination of o-nitrohydrocinnamaldehydes followed by intramolecular catalytic hydrogenation which indeed furnish 3-hydroxy- and 3-aminated THQs in good yields with excellent enantioselectivity/optical purity.